JP2511472B2 - Speed ​​control - improved transdermal delivery device having a Le adhesive - Google Patents

Speed ​​control - improved transdermal delivery device having a Le adhesive

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Publication number
JP2511472B2
JP2511472B2 JP22007287A JP22007287A JP2511472B2 JP 2511472 B2 JP2511472 B2 JP 2511472B2 JP 22007287 A JP22007287 A JP 22007287A JP 22007287 A JP22007287 A JP 22007287A JP 2511472 B2 JP2511472 B2 JP 2511472B2
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Prior art keywords
vinyl acetate
drug
device
acetate content
adhesive
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JPS63119421A (en
Inventor
ス・イル・ユン
デービッド・ジェイ・エンスコアー
ユン・スー・リー
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アルザ・コーポレーション
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Priority to US07/903,002 priority Critical patent/US4938759A/en
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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7092Transdermal patches having multiple drug layers or reservoirs, e.g. for obtaining a specific release pattern, or for combining different drugs

Description

【発明の詳細な説明】 (発明の分野) 本発明は、放出速度制御接着剤を使用する実質上一定の速度で生物学的に活性な薬剤を投与するために皮膚に適用される治療デバイスに関する。 BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to the treatment device to be applied to the skin to administer a biologically active agent at a substantially constant rate using a release rate controlling adhesive .

(発明の背景) 生物学的に活性な剤(以下薬剤という)を実質上一定な速度で皮膚を通して適用するための各種のタイプの包帯に知られている。 Background of the Invention It is known in various types of dressings for application through the skin biologically active agent (hereinafter referred to drug) at a substantially constant rate. 本明細書で使用した「薬剤」とは、 The term "drug" as used herein,
通常有利な生物学的効果を生じさせるため対象に投与される生物学的活性物質として広い概念を持つ。 It is normally administered to a subject to produce a beneficial biological effect a broad concept as the biologically active substance. 米国特許第3598,122(その内容は本発明に包含される)は例えば、背面層、薬剤貯蔵所、放出速度制御膜および皮慮と薬剤とを接触状態に保持する接触接着層からなる多層包帯を記載している。 U.S. Patent No. 3598,122 (the contents of which are encompassed by the present invention), for example, the back layer, drug reservoir, a multilayer bandage comprising a contact adhesive layer which holds the release rate controlling membrane and Kawaomonbaka and drug in contact It describes. その放出速度制御要素はその薬剤とその接触接着層との間に存在しそしてそのデバイスの別の要素を構成する。 Its release rate controlling element constituting the existent and another element of the device between the agent and the contact adhesive layer.

米国特許第4,286,592(その内容は本発明に包含される)はそのデバイスの一つの要素の中に接触接着剤および放出制御膜の両方の機能を組合せることによってこの技術の意義のある改良を記載している。 U.S. Patent No. 4,286,592 (the contents of which are encompassed by the present invention) describes an improvement of the significance of this technology by combining the functions of both the contact adhesive and release control film in one of the elements of the device doing. この発明に従えば接触接着剤層を接触接着剤および放出制御要素の両方として機能させるため、接着剤中、薬剤貯蔵所中におけるその薬剤の拡散係数および溶解度ならびに接着剤の厚さとの関係が存在するに違いない。 To function as both a contact adhesive and release control elements contact adhesive layer according to the present invention, in the adhesive, there is the relationship between the thickness of the agent of the diffusion coefficient and solubility, as well as adhesive agent in the drug reservoir it must be. この関連は便宜上「速度制御接着剤関連」と以下に称される。 This association is referred to for convenience as "rate controlling adhesive related" below.

(i) 接触接着剤層中の薬剤濃度C CA (mg/cm 3 )はその接触接着剤組成物中のその薬剤の溶解度C SCAより大きくない、 (iii) 割 合 (I) the drug concentration of the contact adhesive layer C CA (mg / cm 3) is not greater than the solubility C SCA of the agent of the contact adhesive composition, (iii) percentage は投与期間の実質的な部分にわたって約0.01〜0.7の範囲である。 Ranges from about 0.01 to 0.7 over a substantial portion of the administration period.

式中C CAは接触接着剤組成物中の薬剤の拡散係数(cm 2 The diffusion coefficient of the drug C CA contact adhesive composition wherein (cm 2
/hr)である。 A / hr).

CAはその担体中のその薬剤の拡散係数(cm 2 /hr)である、 C DRは、その薬剤貯蔵所中の薬剤の濃度(mg/cm 3 )である、C SDRはその担体中のその薬剤の溶解度(mg/cm 3 )である、 tは前記投与期間中の時間(hr)である、そして前記期間に適用される「実質上」とは少なくとも50%を意味する。 CA is the diffusion coefficient of the agent of the carrier (cm 2 / hr), C DR , the its is the concentration of drug in the drug reservoir (mg / cm 3), C SDR is in the carrier a drug solubility (mg / cm 3), t is time (hr) in the administration period, and means at least 50% as "substantially" as applied to the period.

その速度制御関連において示された条件が会う時、その接着層の存在において、その薬剤貯蔵層からの薬剤のフラックスはその速度制御関連が0.01である時その接着層を通しての薬剤のフラックスよりも約100倍大きい。 When the condition indicated meet at that speed control-related, in the presence of the adhesive layer, about flux of the drug from the drug reservoir layer than drug flux through the adhesive layer when the speed control-related is 0.01 100 times larger.
その速度制御関連の値が0.7に増加する時、その貯蔵所からの薬剤のフラックスは、その接着剤を通してその薬剤のフラックスに等しい水準まで減少したであろう。 Then the speed control-related value is increased to 0.7 the flux of drug from the reservoir would have decreased to a level equal to the flux of the drug through the adhesive. これは、その速度制御関連はその関連の個々のパラメーター用の値の決定を必要とすることなしに会うかどうかを決定するための単純な実験室テストを提供する。 This is the speed control association provides a simple laboratory test to determine whether meet without requiring determination of the value for its associated individual parameters. 薬剤のインビトロフラックスは貯蔵所および接着剤組成物のサンプル用に測定できる。 In vitro flux of drug can be measured for a sample of the reservoir and adhesive compositions. その貯蔵所フラックスがその接着剤フラックスの約1〜100倍である限り、その関連は満足されるだろう。 As long as the reservoir flux is from about 1 to 100 times the adhesive flux, would the association is satisfied.

この特許において開示された態様の中で、実施例1の態様は、その薬剤貯蔵所および接着剤層の両方において類似のポリイソブチレン/鉱物油(PIB/MO)組成物を利用する。 Among the disclosed aspects in this patent, aspect of the first embodiment, the agent reservoir and similar polyisobutylene / mineral oil in both of the adhesive layers utilize (PIB / MO) compositions. 実施例2の態様はそれぞれ貯蔵所および接着剤として似ていない物質、シリコーン油およびエチレン酢酸ビニル(EVA)コポリマー(9%VA)を利用する。 Aspect of the second embodiment material dissimilar as each reservoir and the adhesive, utilizing a silicone oil and ethylene vinyl acetate (EVA) copolymer (9% VA). 実施例1の態様は構造的完全性および接着剤性質の点で良好な特性を保持し、しかしその特許に開示されたように実施例1のその薬剤貯蔵所および接着剤層を通してその薬剤の拡散係数および溶解度は実質上同じである。 Aspect of the first embodiment holds good properties in terms of structural integrity and adhesive properties, but the diffusion of the agent through the drug reservoir and the adhesive layer of Example 1 as disclosed in that patent coefficient and solubility are substantially the same.

もし実施例においてのようにその薬剤貯蔵所のマトリックス又は担体組成物がその接触接着剤組成物により実質上高い透過性を所有するならば、実質例1のデバイスの放出特性は改良できる。 If the matrix or carrier composition of the drug reservoir as in Example owns substantially higher permeability by the contact adhesive composition, release properties of the device of substantially Example 1 it can be improved. しかしそのようにすることによって構造的完全性および接着特性における幾分かの妥協はなされる。 But some compromise in structural integrity and adhesive properties by doing so is made.

PIB/MO接着剤(本明細書において、鉱物油は天然および合成の鉱物油を包含する)の望ましい特性の一つは多くの薬剤に対して高い透過性である。 PIB / MO adhesives (as used herein, mineral oils include mineral oils of natural and synthetic) One desirable characteristic of a high permeability to many drugs. この理由のため、 For this reason,
本発明前では、本発明者はPIB/MO接着剤との組合せにおいてPIB/MO組成物以外の薬剤貯蔵マトリックス組成物を利用する速度制御接着剤関連に順応する経皮投与デバイスを知らなかった。 In the previous invention, I did not know transdermal delivery device to conform to the speed control adhesive associated utilizing a drug reservoir matrix composition other than PIB / MO composition in combination with a PIB / MO adhesive. 本発明に従えばPIB/MO接着剤の使用に本発明デバイスにおいて可能にし、そして長期間放出特性を改良する似ていない貯蔵所および接着剤組成物の組合せを提供した。 According to the present invention allows the present invention the device for use PIB / MO adhesive and provided the combination of reservoir and adhesive compositions which do not resemble to improve the long-term release characteristics.

従って本発明の目的は放出速度制御接着剤を使用する改良された経皮投与デバイスを提供することである。 Accordingly, an object of the present invention is to provide an improved transdermal delivery device uses a release rate controlling adhesive.

本発明の他の目的は、薬剤投与デバイスを速度制御関連に合致させるPIB/MO接着剤と薬剤貯蔵マトリックス物質との組合せを提供することである。 Another object of the present invention is to provide a combination of a PIB / MO adhesive and drug reservoir matrix material to meet the speed control-related drug administration device.

この発明の他の目的は、チモロールを投与するために経皮投与デバイスを提供することである。 Another object of the present invention is to provide a transdermal administration device for administering timolol.

本発明の他の目的はアトロピンを投与するための経皮投与デバイスを提供することである。 Another object of the present invention is to provide a percutaneous administration device for administering atropine.

本発明のこれらの目的および他の目的は添附図を参照して下記の記載から容易に明らかである。 These and other objects of the present invention are readily apparent from the following description with reference to the accompanying diagrams.

本発明は (a) 不透過性背面体 (b) エチレン/酢酸ビニルポリマー中の薬剤の飽和濃度以上の濃度で前記ポリマー内に分散された前記薬剤からなる薬剤貯蔵所、前記ポリマーは約15〜60%の範囲の酢酸ビニル含量を有し、そして (c) ポリイソブチレン/鉱物油(MO/PIB)接着剤を含む放出速度制御接着層のラミネートを含むことを特徴とした薬剤の経皮投与用治療デバイスに関する。 The present invention is a drug reservoir composed of (a) impermeable back material (b) ethylene / said agent at a concentration of at least the saturation concentration of the drug dispersed in said polymer of vinyl acetate in the polymer, wherein the polymer is from about 15 to having a vinyl acetate content of 60% range, and (c) polyisobutylene / mineral oil (MO / PIB) for transdermal administration of drugs characterized in that it comprises a laminate of release rate controlling adhesive layer comprising an adhesive for the treatment device.

第1図は皮膚に適用される前に包袋10として示される本発明デバイスの基礎的構造を示す。 Figure 1 shows the basic structure of the present invention device shown as tare 10 before being applied to the skin. デバイスの成分は上から不透過性支持体11、担体14中に分散された投与用の生物学的活性な剤を含む薬剤貯蔵所層に(その層は従来公知な透過促進剤、シックナー、安定化剤、および他の添加物を含んでもいても良い)、接触接着層15および不透過剥離可能な被覆又は剥離ライナー16である。 Device components impermeable support from above 11, the drug reservoir layer comprising biologically active agents for administration dispersed in a carrier 14 (the layer conventionally known permeation enhancers, thickeners, stabilizers agent, and may have also include other additives), a contact adhesive layer 15 and impermeable peelable coating or release liner 16. 層16 Layer 16
は包袋10が皮膚に適用される前に層15を露出させるために除去される。 It is removed to expose the layer 15 before the file wrapper 10 is applied to the skin. そのデバイスの特定な薬剤および他の薬剤に応じてある場合には成分の1つ又はそれ以上が蒸発、ブリード、にじみ出ること、漏れ又は露出された側面から出ることを防ぐために包袋10の側面を不透過性被覆又は側面のシールをすることが望ましい。 If you have depending on the particular drug and other agents to evaporation of one or more components of the device, bleed, oozing it, the side of the file wrapper 10 to prevent exit from leaking or exposed side it is desirable to seal the impermeable coating or sides. 支持体11 Support 11
は、貯蔵所12の上面から薬剤が放出されるのを防ぎそして皮膚又は粘膜上それが置かれる時そのデバイス用の保護層被覆として役割を果す。 May serve as a protective layer coating for the device when prevented from the upper surface of the reservoir 12 of the agent is released and on the skin or mucous membranes which it is placed. それは水および薬剤貯蔵所に含まれる物質の両方に対し不透過性でなければならず、そしてこのような支持体を作る適当な物質は従来知られている。 It must be impermeable to both substances contained in water and the drug reservoir and suitable materials for making such supports are known in the art. (米国特許第3,598,122第5欄56−71行参照。薬剤貯蔵所には担体および薬剤の混合物の混合物からなり、そして多くの場合その薬剤は最初その担体物質中に過剰の溶解度で存在する。このような場合において、最初その分布期間全体にわたって活性にその貯蔵所を保持するために溶解した形の薬剤および過剰な不溶な形の薬剤の両方において貯蔵所中に存在する。そのための過剰な薬剤は、その薬剤が分散されている担体が連続相を保持している限り、その担体に含有できる。通常達成できる最大薬剤含有はその貯蔵所の容積の35〜50%の範囲内である。接着剤層においてその薬剤は定常操作では飽和以上の濃度存在しない。 (U.S. consist of a mixture of a mixture of carrier and drug Patent No. 3,598,122 column 5 56-71 see row. Drug reservoir, and in many cases the drug is present in excess of solubility in the first the carrier material. The in cases such as, initially the present in reservoir both in the drug dissolved form throughout the distribution period to hold the reservoir on the activity and excessive insoluble form of the drug. excess drug therefor , its long as the drug carriers are dispersed holds the continuous phase, can be included in the carrier. maximum drug-containing normally achievable in the range 35-50% of the volume of the reservoir. adhesive the agent no concentrations above the saturation in the steady operation in the layer.

米国特許4,286,592号において開示されたように、その接触接着剤が接着と放出速度制御の両方の機能を果すためにその薬剤貯蔵所および接着層は速度制御関連に合致すべきである。 As disclosed in U.S. Patent No. 4,286,592, the drug reservoir and adhesive layers to the contact adhesive performs the function of both the release rate controlling and adhesive should match the speed control-related.

本発明に従えば本発明者は、好ましくは低分子量(LM According to the present invention the present inventors have preferably a low molecular weight (LM
W)PIB(35,000〜50,000粘度平均分子量)および高分子量(HMW)PIB(1,000,000〜1,500,000粘度平均分子量の混合物および25で10〜100CPの粘度を有する天然又は合成の鉱物油からなるPIB/MO接触接着剤を利用する。好ましい混合物はMO35〜65%、LMWPIB10〜40%およびHMWPIB W) PIB (35,000 to 50,000 viscosity-average molecular weight) and high molecular weight (HMW) PIB (1,000,000~1,500,000 viscosity average molecular weight of the mixture and 25 made of natural or synthetic mineral oils having a viscosity of 10~100CP with PIB / MO contact adhesive agent utilized. preferred mixtures MO35~65%, LMWPIB10~40% and HMWPIB
10〜40%からなる。 Consisting of 10% to 40%. これらの組成物は、例えば上述の米国特許第4,286,592号および米国特許第4,262,003号(それらの内容は本発明に包含される)において示されたように経皮投与用のすぐれた接着剤として知られている。 These compositions can, for example U.S. Pat. No. 4,286,592 and U.S. Patent No. 4,262,003 described above (those contents of which are encompassed by the present invention) is known as excellent adhesives for transdermal administration as shown in ing.

本発明に従えば、その薬剤貯蔵所用の担体は約25〜60 According to the present invention, the carrier of the drug reservoir Shoyo about 25 to 60
重量%の酢酸ビニル含量を有するEVAコポリマーを含む。 Comprising an EVA copolymer having a vinyl acetate content of wt%. 好ましい範囲は28〜40%である。 The preferred range is 28-40%. このようなポリマーは、米国特許第4,144,317(その内容は本発明に包含される)に開示されたポリマーを含む。 Such polymers are described in U.S. Patent No. 4,144,317 (the contents of which are encompassed by the present invention) containing polymers disclosed.

本発明の薬剤貯蔵所および接触接着組成物の組合せは多数の経皮投与可能な薬剤を投与させるために使用できる。 Drug combination reservoir and contact adhesive compositions of the invention can be used to administer a large number of transdermal administrable drug. この発明から最大の利益を得るためにその薬剤はPI The agent PI in order to obtain the maximum benefit from the invention
B/MO接着層を通しての拡散係数よりも高いEVA貯蔵所を通しての透過度を有するべきである。 It should have a permeability through high EVA reservoir than the diffusion coefficient through the B / MO adhesive layer. 鉱物油に適度に溶解し(例えば10mcg/cm 3 −5mg/cm 3の溶解度)、そして50 Moderately soluble in mineral oil (e.g. solubility of 10mcg / cm 3 -5mg / cm 3 ), and 50
℃以上の融点を持つ薬剤が特に好ましい。 Agents with a melting point above ℃ is particularly preferred. その薬剤はチモロール、フェンタニール、アトロピン、クロニジン、 The drug is timolol, fentanyl, atropine, clonidine,
プロプラノロール、イソソルビドジニトレート、スコポラミン、エストラジオール、フェニルプロパノールアミン、クアナベンズ、ワアバイン、サルブタモール、ラベトロール、ハロペリドール、プロモクリプチン、エファドリン、クロロフェニラミン、およびメトリホネートを包含する。 They include propranolol, isosorbide dinitrate, scopolamine, estradiol, phenylpropanolamine, Kuanabenzu, Waabain, salbutamol, labetolol, haloperidol, bromocriptine, Efadorin, chlorpheniramine, and metrifonate.

本発明の一般的な記載において下記の実施例が提供される。 The following examples are provided in the general description of the present invention.

実施例1 チモロールの経皮投与はPHVlasses,“Initial Eval Example 1 timolol transdermal administration PHVlasses, "Initial Eval
uation of Transdermal Timolol:Serum Concentration uation of Transdermal Timolol: Serum Concentration
and B−Blockade,"Journal of Cardiovascular Pharmac and B-Blockade, "Journal of Cardiovascular Pharmac
ology,7:245−250(1985)によって安全でかつ効果のあることが記載された。 ology, 7: has been described that a safe and effective by 245-250 (1985). 本発明による経皮モチロール経皮デバイスは剥離ライナーおよび支持体上塩化メチレンからの接着剤組成物の溶剤流し込みおよび表1に記載された薬剤貯蔵所組成物の押出しおよびそのように形成された2つの要素のラミネートによって構成される。 Transdermal Mochiroru transdermal devices according to the present invention is a release liner and a support on the adhesive composition from methylene chloride solvent casting and drug reservoir composition described in Table 1 extrusion and so formed of two It constituted by laminating elements.

(その油は保存中薬剤貯蔵所から接触接着剤に浸透し適当な平衡濃度およびカッコで示された接着剤厚さに達する) EVA40およびその接着剤を通してのチモロールの32℃ (The oil reaches the indicated adhesive thickness penetration by appropriate equilibrium concentration and brackets to the contact adhesive from the storage in the drug reservoir) EVA40 and 32 ° C. of timolol through the adhesive
での拡散係数は、それぞれ約6.4×10 -6 cm 2 /hrおよび1.4 Diffusion coefficient at from about 6.4 × 10 -6, respectively cm 2 / hr and 1.4
×10 -5 cm 2 /hrであった。 × was 10 -5 cm 2 / hr. EVA40およびそのPIB/MO接着剤中のチモロールの32℃の溶解度はそれぞれ108mg/cm 3および11mg/cm 3であった。 EVA40 and 32 ° C. in solubility timolol during its PIB / MO adhesives were respectively 108 mg / cm 3 and 11 mg / cm 3. 治療上のおよび無限のシンク(sink)内へ直接32℃でのインビトロ放出速度のテストは第2図に示された薬剤貯蔵所および接着剤の両方のための対照PIB/MO組成物を使用してテストされた。 In vitro release rate tests at direct 32 ° C. to therapeutic and infinite sink (sink) in uses control PIB / MO compositions for both the drug reservoir and adhesive shown in Figure 2 It was tested Te.

実施例2,3および4 チモロール投与デバイスの態様は塩化メチレンからの溶剤流し込みおよび表2に示される組成物を実施例1記載の方法で押出し構成された。 Aspect of Examples 2, 3 and 4 timolol delivery devices were extruded composed solvent casting and methods of the composition described in Example 1 shown in Table 2 from methylene chloride.

35℃でのインフイニットシンク(infinitesink)内へこのようなデバイスのインビトロ放出速度は第3図に示される。 At 35 ° C. to inflation init sink (infinitesink) in vitro release rates of such devices are shown in Figure 3. そのデバイスはボランティアな人に適用されそして1週間保持された。 The device has been applied to human volunteers and held for one week. 定期的に血液サンプルが採集されそしてチモロール含有量の分析が行なわれた。 Regular blood samples were collected and analyzed for timolol content is performed. その結果は第4図に示される。 The results are shown in Figure 4.

実施例2から得られたチモロール濃度は20〜168時間約15〜26%の範囲内の心拍数を減少させるのに十分であった。 Timolol concentrations obtained from Example 2 was sufficient to reduce the heart rate in the range of 20 to 168 hours at about 15 to 26%.

実施例5 表3の組成を有するアトロピン投与デバイスからのインフィニットシンク内への治療上インビトロ放出速度は第5図に比較された。 Therapeutically vitro release rates into the Infinite sink from atropine delivery device having the composition of Example 5 in Table 3 were compared in Figure 5.

EVA40およびPIB/MO組成物における32℃でのアトロピンの透過性は、それぞれ1.3×10 -1 mcg/cm/hrおよび5.4 Permeability atropine at 32 ° C. in EVA40 and PIB / MO compositions, respectively 1.3 × 10 -1 mcg / cm / hr and 5.4
×10 -2 mcg/cm/hrと推定される。 × is estimated that 10 -2 mcg / cm / hr. EVA40−鉱物油貯蔵所組成物の32℃でのアトロピン塩基の透過性は3.0×10 -1 mcg Permeability of atropine base at 32 ° C. of EVA40- mineral oil reservoir composition 3.0 × 10 -1 mcg
/cm/hrと推定される。 It is estimated that / cm / hr. アトロピンは治療血液水準の遅滞時間を減少させるため接着剤中に含まれる。 Atropine is included in the adhesive to reduce the lag time of the therapeutic blood levels.

上述の本発明の記載は変更可能であり、以下の特許請求の範囲によってのみ本発明は限定される。 The foregoing description of the present invention may be varied, the present invention only by the following claims is limited.

【図面の簡単な説明】 BRIEF DESCRIPTION OF THE DRAWINGS

第1図は本発明の態様の断面図である。 FIG. 1 is a cross-sectional view of the embodiment of the present invention. 第2図はEVA40貯蔵所−PIB/MO接着剤の実施例1からの放出速度データを示すグラフであり、本発明のチモロール投与デバイスを使用し、現実の投与量とインビトロ放出速度との比較を示す。 Figure 2 is a graph showing the release rate data from Example 1 of EVA40 reservoir -PIB / MO adhesive, using timolol administration device of the present invention, the comparison of the actual dose and in vitro release rates show. 第3図はこの発明の態様のインビトロ投与特性のプロットを示す。 Figure 3 shows a plot of in vitro administration characteristic aspect of the present invention. 第4図は本発明の態様から得られたインバイボプラズマ水準のプロットを示す。 Figure 4 shows a plot of the inverter warts plasma levels obtained from embodiments of the present invention. 第5図は異なった薬剤貯蔵所(32℃)を持ったTRP−18 Figure 5 is different drug reservoir (32 ° C.) to have the TRP-18
系(PIB/MO貯蔵所および接着剤を持つ本発明のアトロピン投与デバイスの治療インビトロ放出速度対時間の関係を示すグラフである。 System (which is a graph showing the relationship between treatment vitro release rates versus time of atropine administration device of the present invention having a PIB / MO reservoir and adhesive.

───────────────────────────────────────────────────── フロントページの続き (72)発明者 ス・イル・ユン アメリカ合衆国カリフォルニア州94021, ロス,アルトス,ラニーミード・コート 1021 (56)参考文献 特開 昭61−145113(JP,A) 特開 昭61−158924(JP,A) 特開 昭56−125311(JP,A) ────────────────────────────────────────────────── ─── of the front page continued (72) inventor vinegar Il Yoon United States, California 94021, Los, Altos, runnymede Court 1021 (56) reference Patent Sho 61-145113 (JP, a) JP Akira 61 -158924 (JP, A) JP Akira 56-125311 (JP, A)

Claims (16)

    (57)【特許請求の範囲】 (57) [the claims]
  1. 【請求項1】(a)不透過性支持体 (b)エチレン/酢酸ビニルポリマー中の薬剤の飽和濃度以上の濃度で前記ポリマー内に分散された前記薬剤を含む薬剤貯蔵所、前記ポリマーは約15〜60%の範囲内の酢酸ビニル含量を有し、そして (c)ポリイソブチレン/鉱物油(MO/PIB)接着剤を含む放出速度制御接着層のラミネートを含むことを特徴とした薬剤の経皮投与用治療デバイス。 1. A (a) impermeable support (b) an ethylene / at concentrations above the saturation concentration of the drug in the vinyl acetate in the polymeric drug reservoir containing dispersed the drug in said polymer, said polymer is from about having a vinyl acetate content in the range 15 to 60% and (c) after the drug characterized in that it comprises a laminate of a polyisobutylene / mineral oil (MO / PIB) comprising an adhesive release rate controlling adhesive layer leather administration for the treatment device.
  2. 【請求項2】前記酢酸ビニル含有は約28〜40重量%の範囲である特許請求の範囲第1項記載のデバイス。 Wherein said vinyl acetate content is about 28 to 40 wt% of the claims devices ranging first claim of the range.
  3. 【請求項3】前記薬剤は始めは飽和以上の濃度で前記貯蔵所中に存在する特許請求の範囲第1項記載のデバイス。 3. The device of the drug is initially described first term claims present in said reservoir at a concentration above saturation.
  4. 【請求項4】前記薬剤は鉱物油に適度に可溶であり、そして約50℃以上の融点を有する特許請求の範囲第1項記載のデバイス。 Wherein said drug is moderately soluble in mineral oil and claimed devices ranging first claim of having about 50 ° C. above the melting point.
  5. 【請求項5】前記薬剤はチモロール、フェンタニール、 Wherein said medicament is timolol, fentanyl,
    アトロピン、クロニジン、プロプラノロール、イソソルビドジニトレート、スコポラミン、エストラジオール、 Atropine, clonidine, propranolol, isosorbide dinitrate, scopolamine, estradiol,
    フェニルプロパノールアミン、ウァバイン、サルブタモール、クアナベンズ、ラベトロール、ハロペリドール、 Phenylpropanolamine, Wabain, salbutamol, Kuanabenzu, labetolol, haloperidol,
    ブロモクリプチン、エフェドリン、クロロフェニラミンおよびメトリホネートからなる群から選ばれる特許請求の範囲第1項記載のデバイス。 Bromocriptine, ephedrine, chlorpheniramine and claims device ranges claim 1 wherein the selected from the group consisting of metrifonate.
  6. 【請求項6】その貯蔵所における前記薬剤の濃度は24時間〜7日間の期間単位活性で前記担体においてその薬剤の活性を保持するのに十分である特許請求の範囲第1項記載のデバイス。 6. The device of that concentration of the drug in reservoir is described range first term of sufficient claims to retain the activity of the agent in the carrier with period unit activity of 24 hours to 7 days.
  7. 【請求項7】前記薬剤はチモロールの塩基である特許請求の範囲第1項記載のデバイス。 7. The device of the agent ranges first claim of claims is a base of timolol.
  8. 【請求項8】前記エチレン酢酸ビニルコポリマーは約28 Wherein said ethylene-vinyl acetate copolymer is from about 28
    〜40%の酢酸ビニル含量を有する特許請求の範囲第7項記載のデバイス。 It claims Devices ranging seventh claim of having a 40% vinyl acetate content.
  9. 【請求項9】前記酢酸ビニル含量は約40%である特許請求の範囲第8項記載のデバイス。 Wherein said vinyl acetate content device eighth Claims claims about 40%.
  10. 【請求項10】前記薬剤はアトロピンの塩基である特許請求の範囲第1項記載のデバイス。 10. The device of the agent ranges first claim of claims is a base of atropine.
  11. 【請求項11】前記エチレン/酢酸ビニルコポリマーは約28〜40%の酢酸ビニル含量を有する特許請求の範囲第 11. The claims with the ethylene / vinyl acetate copolymer is from about 28 to 40% vinyl acetate content of
    10項記載のデバイス。 Device 10 Claims.
  12. 【請求項12】前記酢酸ビニル含量は約40%である特許請求の範囲第11項記載のデバイス。 12. The method of claim 11, wherein the vinyl acetate content device claim 11 wherein the appended claims is about 40%.
  13. 【請求項13】前記エチレン/酢酸ビニルコポリマーは約28〜40%の酢酸ビニル含量を有する特許請求の範囲第4項記載のデバイス。 Wherein said ethylene / vinyl acetate copolymer is from about 28 to 40% of the claims devices ranging fourth claim of having a vinyl acetate content.
  14. 【請求項14】前記酢酸ビニル含量は約40%である特許請求の範囲第13項記載のデバイス。 14. The vinyl acetate content device 13 Claims claims about 40%.
  15. 【請求項15】前記エチレン/酢酸ビニルコポリマーは、約28〜40%の酢酸ビニル含量を有する特許請求の範囲第5項記載のデバイス。 15. The method of claim 14, wherein the ethylene / vinyl acetate copolymer, about 28 to 40% of the claims devices ranging fifth claim of having a vinyl acetate content.
  16. 【請求項16】前記酢酸ビニル含量は約40%である特許請求の範囲第15項記載のデバイス。 16. The vinyl acetate content device Claims paragraph 15, wherein about 40%.
JP22007287A 1986-09-02 1987-09-02 Speed ​​control - improved transdermal delivery device having a Le adhesive Expired - Lifetime JP2511472B2 (en)

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US07/903,002 US4938759A (en) 1986-09-02 1986-09-02 Transdermal delivery device having a rate controlling adhesive
US903002 1986-09-02

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EP0259136A3 (en) 1989-03-15
JPS63119421A (en) 1988-05-24
DE3767412D1 (en) 1991-02-21
EP0259136B1 (en) 1991-01-16
GR3001328T3 (en) 1992-08-31
CA1297754C (en) 1992-03-24
US4938759A (en) 1990-07-03
EP0259136A2 (en) 1988-03-09

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